Summary: Facial clefts are one of the most common birth defects, affecting 2 out of every thousand babies. While the main causes of facial clefts are unknown, it is obvious that genetics plays a strong role. We've shown that families with one member affected by clefts are 40 times as likely to have a baby with a cleft. Environmental factors are also presumed to play a role in clefts. For example, clefts are easily produced in experimental animals exposed to teratogens. It is likely that humans vary in their genetic susceptibility to teratogens that cause clefts. More than two decades ago, we anticipated that genetic susceptibility would become an important area of epidemiologic research at NIEHS. Accordingly, we selected facial clefts as a condition with both genetic and environmental causes, and we began in 1992 to develop a study to address the causes of clefts. In 1996 we launched a population-based case-control study of facial clefts in Norway. (Norway has one of the highest rates of cleft lip and palate in the world.) The field phase was completed in 2002. We enrolled 88% of all babies with facial clefts born in Norway between 1996 and 2002 (574 cases), and 76% of eligible control infants (763) selected randomly from the population. Mothers of these infants provided detailed information on occupational and other exposures during pregnancy, as well as on nutrition, personal habits and medical history. Biological samples for DNA analysis were collected from cases and controls as well as their mothers, fathers and siblings. These total nearly 4000 people. DNA has been extracted from these samples and assayed for GWAS. We have also had DNA from our newborn cases and controls assayed for methylation changes. We had earlier reported that womens passive exposure to cigarette smoking by others was associated with facial clefts. This is an important question, in that no birth defects have previously been shown to be caused by passive smoke exposure. However, our study by itself did not have enough statistical power to provide a definitive answer. We therefore collaborated with a number of other studies of facial clefts that had collected information on passive smoke exposure. While each study was in general too small to provide a sound answer, the combination of studies showed a clear (and statistically significant) pattern of increased risk of facial clefts after mothers passive smoke exposure during pregnancy (1). Facial clefts show strongly familial patterns. Parents with clefts have about 40 times greater chance of having a baby affected by facial cleft than other parents. Risk is similarly elevated among the siblings of an affected child. These are among the largest familial risks of any birth defect, and strongly suggest that genetic factors are at work. We have therefore put much attention into the genetic study of children with facial clefts first within our own study of facial clefts in Norway, and then in collaboration with other studies of facial clefts in the US and Europe. While we have identified an array of genetic variants that are consistently associated with facial clefts (2-4), the proportion of all clefts explained by these genes remains frustratingly small.